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2,411,019
Patented Nov. 12, 1946
UNITED STATES mraur OFFICE»
2,411,019
METHOD OF FORMING CARBOXYLIC ACID
SUBSTITUTED'AMINES
>
Frederick C. Bersworth, Verona, N. J.
No Drawing. Application May 1, 1943,
Serial No. 485,343
'
5 Claims.
(Cl. 260-112)
1‘ .
This invention relates to chemistry and more
particularly to organic chemistry and has for
its object the provision of a method of convert
ing the alpha amino acid content of naturally oc
curring protein materials, such as casein, al
bumin, soy bean meal, beet sugar residues, and
protein molecule which consists of a plurality of
molecules of glycine
‘
H-CH-COOH
NH:
"
bound together by peptide linkages extending be
tween the alpha amino nitrogen group of one
glycine molecule and the carboxylic acid group
Another object is to provide a method of re
of another glycine molecule. This peptide link
covering the alpha amino acid content of protein 10 age is generally indicated as follows:
materials in the form of carboxylic acid sub
—-OC-CH-X
stituted amines.
NH-oc-cH-x
NH~—
Still another object is to provide a method of
the like, into commercially useful amino com
pounds.
producing carboxylic acid substituted amines.
Other objects will be apparent as the invention
is more fully hereinafter disclosed.
This application is a continuation-in-part ap
plication of my application Serial No. 363,109
?led October 24, 1940, now issued as Patent
(wherein X=H or the remainder of the amino
acid attached to the alpha CH group).
When this protein molecule is hydrolyzed 11+
and OH- ions enter into the peptide linkages
(NH-0C) between adjacent glycine molecules
2,318,046 dated May 4, 1943, which application 20 converting the same to NHz and COOH groups
is assigned to the same assignee as the present
respectively. In the absence of a basic metal ion
application.
the NH: and COOH groups of each glycine mole
In accordance with these objects I have dis
covered that when a protein molecule is hy
cule react together'to form an ammonium salt,
but in the presence of a basic oxide-0r hydroxide
drolyzed in the presence of a basic metal oxide 25 capable of displacing the acid hydrogen, the car
or hydroxide, the peptide linkages (—NH—'OC—)
boxylic acid group reacts to form a metal salt.
between the plurality of alpha amino acid
With the NaOH, for example, the sodium salt
molecules of which the protein molecule consists,
are broken up and that the carboxylic acid group
of the resultant alpha amino acids are stabilized 30
by conversion to a metal salt thereby releasing
is formed with liberation of H20.
the alpha amino nitrogen group for reaction with
Other metal oxide and hydroxides, the metal
an amino hydrogen of an amino nitrogen group
constituent of which is, capable of displacing acid
hydrogens, react similarly as will be apparent
of an aliphatic amine whereby ammonia (NIH)
is liberated with the substitution of the carboxylic 35 to one skilled in the art. However, the more
strongly basic metal oxides and hydroxides are
acid salt residue of the amino acid onto the
preferable as will hereinafter appear.
amino nitrogen of the amine resulting in the
In the presence of an aliphatic primary or sec
formation of a substituted amine. Accordingly,
by varying the extent to which the protein mole
ondary amine that contains at least one amino
cule is degraded or split up into shorter chain 40 nitrogen group having at least one displaceable
amino hydrogen which amino nitrogen group is
length groups of peptide-linked molecules of the
alpha amino acids, a plurality oi’ substituted » attached directly to an aliphatic carbon, the metal
amines from the same amine may be obtained
, salt of the alpha amino acid reacts therewith with
liberation of ammonia (NHa) to form a carbox~
containing carboxylic substituent groups'of vary
ing chain length ranging from a chain length 45 ylic acid substituted amine in which the substitu
ent carboxylic group for each amino hydrogen of
equivalent to that of a single amino acid mole
the amine consists of the carboxylic acid salt resi
cule up to a chain length equivalent ‘to a large
due of the amino acid after the removal there
number of amino acid molecules joined together
by peptide-linkages with the’end carboxylic acid ' I from of the alphaamino nitrogen group. This re
group‘ of the chain stabilized as the metal salt ?oilaction proceeds as follows:
of a basic metal and the opposite end group minus ‘
<1) Secondary amine , ‘
the alpha amino group and attached to the amino
nitrogen group of the amine.
,
'
'
The reaction‘ involved in the present invention
-' may be most simplyillustrated in the case of a 55
R
.
H-CH-COONa + N-R-R'= \N-H-CH-COQNB +‘NH;
N31.
H
‘a?
“
'
"
2,411,019
2
H-CH-COON
I
NH:
(2) Primary amine
~
H
n-on-coom
a) + \\N-R=R-N/
>
+ ZNHI
/
H
H-CH-COONB
(3) Polyamine (iii-amine)
NH:
(
conditions leads to this conclusion, and it is my
belief that the [decompositionof the peptide link
age is one of hydrogenation rather than by hy
drolysis.
i‘ ‘
-
,
In accordance with the present invention,
therefore, it is contemplated subjecting the pro- I
tein moleculeto the action of a basic metal oxide
or hydroxide in an aqueous solution of‘an ali
phatic amine containing at least one amino nitro
10 gen group attached directly to an aliphatic car
bon in which group there is at least one displace
~R-N
+ ma,
able amino hydrogen, at a temperature at which
\n-on-o'ooNs
the reaction proceeds at an economically practi
Na00C-CH.H
H-CH-COONa
NaOOC-CH-H
In'the above equations R equals the residue of
cal rate, controlling the extent of degradation of
an aliphatic amine that contains at least one 15 the protein molecule by regulating the time of the
reaction to obtain partial to complete degrada
amino nitrogen group, the said residue contain
ing an aliphatic carbon bound directly to the
tion of the protein molecule with the resultant
formation with any given amine and protein long
amino nitrogen N; R’ equals a group substituted
chain carboxylic substituent groups containing a
for one amino hydrogen; R2 equals (CH2)n where
n equals at least 2; and in the formula 20 plurality of amino acid molecules bound together
by peptide linkages having the carboxylic group
>
H-CIlH-COONa
of the amino acid molecule at one end of the chain
neutralized by a basic metal ion and the alpha
amino group of the amino acid molecule at the
NH:
for the amino acid salt, “X” may be present as
a substituent group for the H attached to the 25 opposite end displacedwith resultant substitution
alpha carbon group (CH) and any other basic
of thechain at the alpha CH group of the mole
metal ion M may be present in place of Na in
cule onto the amino nitrogen of the amine in
the carboxyl group. Alanine, for example,
"
These compounds generally may be indicated
by the formula:
omen-coon
_
place of an amino hydrogen.
NH:
contains a CHa- group in substitution for the
H bound to the alpha CH group present in
glycine, and leucine, as another example, con
tains the complex group
CH:
OH-OHa
c
.
in‘ substitution for this same n in glycine. In
view thereof, alpha amino acids generally may
be written
,
X-(IJH-COOH
NH:
wherein X equals hydrogen or a group substituted
therefor onto the alpha OH group.
Heretofore in the art, hydrolysis of protein in
wherein R equals the remainder of an aliphatic
amine containing at least one amino nitrogen
45 attached directly to an aliphatic carbon; R’ equals
a substituent group for one amino hydrogen; M
equals a metal ion; and x equals the remainder
of the alpha amino acid molecule attached to
the presence of a basic oxide has been effected.
the alpha CH group of the said acid.
Such hydrolysis procedure results in considerable 50 In the above equations the chain length in
oxidation of the hydrolysate product which is un
cluded within theparenthesis may consist of n
desirable in that decomposition of the complex
atoms where n equals zero or any number less
structures of which the group X may be com- _
than the total number of atoms included within
prised in the formula
the protein molecule. As a practical matter, the
x- 011-0 0 on
NH: ‘
55 number 11. becomes a number very much less than
the total number of amino acid molecules in
cluded within a protein molecule, for the reason
.is usually effected with resultant loss of valuable
that the total, amount of splitting of the plu
organic compounds.
rality of peptide linkages cannot be controlled or
When such hydrolysis, however, is conducted 60 regulated within close limits. However, by vary
in the presence of an aliphatic amine, oxidation
of the hydrolysates or of the "1!” structure of the
alpha amino acids comprising the protein mole
cule is substantially eliminated, due, it is believed,
ing the time interval of reaction to be short, me
dium and prolonged time intervals, substituted
carboxylic amines containing substituent groups
having a. large number of peptide-linked amino
to the fact that the reaction tends to go in the 65 acid groups, a smaller number of peptide-linked
direction of metal amide formation as an interme
groups and substantially no peptide-linked groups
diate reaction product liberating nascent hydro
may be obtained.
gen for the reduction of the alpha amino group of .
As an illustration of the practice of the pres
the amino acid. Thereafter when the metal of
ent invention, a determined weight of a pro
the amide is displaced during the substitution re 70 tein, for example, 500 grams of casein, suspended
action, reducing instead of oxidizing conditions
in 5000 c. 0. H20 containing 500 grams of di prm
are maintained in the solution by the presence 01’
the free metal ion or by its reaction with water to
form oxide or hydroxide. This may not be the
pyl amine, and 250 grams of a caustic alkali such
as NaOH, when heated to a re?uxing tempera
ture of about 110° C. under conditions excluding
true explanation but the absence of oxidation 75 atmospheric oxygen, for example, in a container
2,411,019
5
.
provided with a re?uxing condenser opening, from
' ken.
6
.
.
Where the time interval of heating is short- ’
the condenser to the air through a one-way'valve ,
ened to a fraction of this maximum. time‘ inter
permitting the escape of uncondensed gases to
the atmosphere at a detemiined positive pres
sure, will when heated for varying time inter
vals rangingfrom 5 hours to 20. hours, produce
the sodium salt of substituted carboxylic amines
wherein the substituent carboxylic group is of
varying chain length decreasing with increase in
the time of heating.
10
val, intermediate poly-meric carboxylic substit- I
‘ The amount of the amine added to the above
solution is in large excess or that theoretically
required to react with the total number of alpha
amino acid molecules present in the protein, and
the amount of caustic alkali present is in excess 15
uent groups are obtained.
_
The protein casein has been reported'as con
sistingyin large part, of glutamic acid
cans-N112- (000K) 2
However, when treated as above described and
'reacted with an amine to the extent destroying
all peptide-linkages the carboxylic acid substitu
ent product obtained consists mainly of the acid
complex (CH3) 2'CH'CH2-CH' (NHz) COOH, indi
cating that the main alpha amino acid‘constitu
ent of casein is the acid leucine. '
~
of the total amount of such alkali required to
However, a considerable number of other alpha
effect neutralization of all of the carboxylic acid
amino acids are present in casein and the mixture
groups present in the plurality of alpha amino
of tetra carboxylic acid substituted diamines ob
acid molecules present in the said protein. The
tained by the practice of ‘the above described
amount of the excess amine and caustic alkali 20 invention appears to have many valuable prop
erties not normally present in a substantially
may be varied widely without essential departure
from the present invention, as such excess insures
pure tetra carboxylic diamine, such as that ob
tainable by the reaction of» the substantially pure
the progress of thereaction in the direction of '
carboxylic substitution.
metal salt of glycine;
_
In general, in the above described method of
converting the alpha amino acid content of pro
tein into substituted carboxylic amines wherein‘
25
.the substituent group consists of from one to a ‘
‘
with the diamine.
7
.
H-(FH-COONB)
NH:
,
~
'
The tetra carboxylic acid substituted diamines
plurality of alpha amino acid molecules termi
nating at one end in a carboxylic salt of a basic 30 formed as above indicated may be recovered from
the aqueous solution by acidifying the solution
metal and at the other end in a CH group bound
to the amino nitrogen of an aliphatic-amine, the
amount of water to be employed with any given
protein is preferably that which is 'su?icient to
maintain a liquid phase reaction between the pro
tein and the'amine. Inthe case of amines that
are insoluble in the aqueous solution present, I
may employ a non-reactive solvent such as a ter
tiary alcohol to form an amine solution that is
with a strong mineral acid such as HCl or E804
to a pH at which the acid is least soluble and
separating the precipitated acid from the metal
35
salt solution. The tetra acid compounds are sub
stantially‘insoluble in cold water but are soluble
'in acid and alkali solutions and are generally
solubilized by any- metal ‘oxide, hydroxide or
carbonate, the metal constituent of which is capa
Also in the 40 ble of displacing an acid hydrogen. Many differ
ent inorganic and organic compounds may be
case of an amine that exists in the vapor state
formed from these tetra carboxylic substituted
at the temperature of re?uxing. I may feed the
miscible with the water solution.
amine into the heated solution at a rate which
amines for use in a plurality of di?erent ways.
The tetra carboxylic substituted diamines in
solution. Various ‘other modi?cations of the 45 which the substituent group consists of a chain
consisting of a, plurality of peptide-linked alpha
practice outlined above may be made without es-‘
amino acid molecules having the carboxylic group
sential departure from the present invention as
of one end molecules stabilized by a basic metal
one skilled in the art will recognize.
ion and the opposite end molecule minus its
The most useful of the carboxylic acid substi
tuted amines producible by the practice of the 50 alpha amino group and connected at the alpha
CH group directly to the ‘amino nitrogen of the
present invention are‘the tetra carboxylic acid
amine, are essentially unstable‘ compounds, sub
substituted amines obtainable by reacting an
ject to the hydrolytic splitting up of the several
aliphatic diamine conforming to the structure
peptide linkages contained therein and to further
NHz- (CHzin-NHz wherein it may be the numeral,
2, 3, 4, 5, etc., with the protein as above disclosed. 55 substitution therein of an amino nitrogen linkage
between the peptide-linked molecules in accord
Ethylene diamine, tri methylene diamine, tetra
ance with the method disclosed and claimed in
methylene diamine,- penta methylene diamine,
co-pending application Serial No. 485,344, ?led
etc., are typical examples of such diamines.
May 1, 1943, which application is assigned to the
These tetra carboxylic acid substituted amines
have chemical and physical properties that adapt 00 same assignee as the presentapplication, to form
long chained resinous—like amino acid substituted
the, same for extensive use as de-ionization agents
amino complexes of great utility in the art of
in water solutions, as extenders and plasticizer
forming arti?cial ?bers and threads for the pro
agents in association with natural and arti?cial
duction of spun and woven products. ,
polymers of rubber-like structures, and in var
ious other ?elds of use, and as intermediates in 65 In the practice of vthe present invention, in
place of caustic alkali or in addition to caustic
organic synthesis reactions generally.
a‘kali, substantially any metal oxide or hydroxide
When ethylene diamine, for example, is added
whose metal ion is capable of displacing acid
to the alkaline solution above described, in an
hydrogens from the carboxylic acid group may
amount providing one molecule of the diamine
for each four (4) molecules of alpha‘amino acid 70 be ‘employed. For example, an alkaline earth
metal oxide or hydroxide, or a, heavy metal oxide
molecules present in the protein, the mono meric
or hydroxide such as iron oxide or hydroxide or
tetra‘ carboxylic acid (Na salt) substituted di-.
various mixtures of metal oxides and hydroxides
amine is obtained where the time of reaction is“
may be employed, if desired. Beryllium oxide
extended to the point where the biurette test
shows that all the peptide-linkages have been bro 75 and hydroxide and various alkali metal com’
permits complete absorption of the amine in the
9,411,019
7
8
,
reconstituted during hydrolysis and the amount
pounds with other metal oxides such as plum
bates, beryllates, vanadates, molybdates, etc., may
alternatively be employed to good advantage in
of said organic base being in large excess or that ‘
' amount providing at least .one displaceable amino
the present invention. In general, however, I
hydrogen for each alpha amino nitrogen group
' have found it preferable to employ an alkali metal
hydroxide as the alkali metal‘salts- of the amino
of the neutralized reconstituted- alpha amino
acids, the time interval of heating being select
acids are not only the most soluble but are also
the most stable of the metal salts under the con
, the neutralized alpha amino acid hydrolysate
ditions of reaction and moreover produce readily
product for substitution reaction with said or
ed to provide the said desired chain length in
soluble salts with strong mineral acids‘ facilitating 10
subsequent precipitation and puri?cation of the l
ganic base.
.
2. The method of converting the alpha amino
‘ tetra carboxylic substituted diamine.
- acid content of protein materials into carboxylic
acid substituted amines having a determined
In place of casein, any of the naturally occur-_
ring protein materials may be used, such ‘as soy
chain length protein hydrolysate substituent
bean meal, ‘sugar beet residues, albumin, etc. 15 group therein, which comprises‘ suspending a
Theparticular carboxylic substituent group ob
tained by the use of these different proteins will,
of course, vary with the particular protein em
known weight of the protein in‘ water, adding
thereto an amount or an inorganic base at least
su?icient to neutralize substantially all of the car
boxylic acid groups contained in the alpha amino
ployed, depending‘ upon ' the particular alpha
amino acid or acidsof which the protein molecule 20 acid content of said protein material and an
is comprised. The basic reaction resulting in the
amount of ‘an aliphatic amine containing at
‘ splitting up of the peptide-linkage with resultant
least one amino nitrogen group having at least
displacement of the alpha amino nitrogen group
one displaceable amino hydrogen therein, said
of the amino acid and the :formation of a car
amount being in large excess of that amount pro
boxylic substituted amine wherein the substituent 25 viding one displaceable hydrogen for each alpha
group is the carboxylic residue of the amine acid
amino nitrogen group of the alpha amino acids
and may consist of a plurality of peptide-linked
present in said protein material, and heating
molecules of the amino acid, as hereinabove de
said suspension to a re?uxing temperature under
scribed, however, remain the same.
' a positive pressure of the uncondensed gases
The above indicated reaction resulting in the 30 evolved from said suspension su?icient only to
formation of carboxylic substituted amines upon
prevent the entry of atmospheric gases to the
the hydrolysis of alpha amino acid molecules
reacting compounds of said suspension, venting
, joined together by Peptide-linkages in the pres
the excess pressure of the said uncondensed gases
ence of a basic metal oxide or hydroxide and in
to the atmosphere, for an extended period of time
the presence of an aliphatic amine having at 35 providing the said determined chain length pro
least one amino group withat least one displace
_ tein hydrolysate substituent group.
able amino hydrogen, is characteristic of all
alpha amino acids existing in molecular form or
in chain form as a result of peptide-linkage, such
as protein or synthetic peptide-compounds, and 40
insofar as the present invention is concerned
peptides and poly peptides of an alpha amino
acid, such as the well known di keto piperazine‘
condensation products, are substantial equiva
lents for protein.
-
'
v
3. The method of converting the alpha amino
acid content of casein into carboxylic acid sub
stituted amines having a mono to poly molecu
lar chain length protein hydrolysate substituent
group therein, which comprises suspending a,
known weight of the casein in water, adding
thereto a caustic alkali and an aliphatic amine
containing at least one amino nitrogen group
45 having at least one displaceable amino hydrogen
Having hereinabove described the present 111-:
therein, and heating the suspension to a re?uxing
vention generically and speci?cally and given two
speci?c examples of the practice of the same it is
temperature under a positive pressure of the un
condensed gases evolved from the suspension
su?icient only to exclude atmospheric gases from
believed apparent that the same may be widely
varied without essential departure therefrom and 50 the heated suspension, the excess of said uncon
densed gases being vented to the atmosphere, the .
all such are contemplated as may fall within the
amounts of said caustic alkali and said aliphatic
scope of the following claims.
‘
_
amine relative to the amount of said casein be
' What I claim is:
ing at least sufficient to provide for the complete
1. The method of treating protein materials
to convert the alpha amino acid contentvof the 65 neutralization by said caustic alkali of all car
boxylic acid groups in the alpha amino acid hy
protein into metal salts of carboxylic acid sub
drolysate product of the said casein and to pro
stituted amines having a desired mono to poly
vide a large excess of the amine over that pro
molecular chain length protein hydrolysate sub
viding‘ at least one displaceable amino hydrogen
stituent group therein, which comprises suspend
ing the protein in water‘ and hydrolyzing the al 60 for each alpha amino group in the said alpha
amino acid hydrolysate product of the said
pha amina acid content of the protein in the
casein, andv the time interval of heating being
presence of an inorganic base and an organic
extended to that providing the desired mono to
base consisting of an aliphatic amine ‘having at
poly molecular chain length of neutralized pro
least one amino nitrogen group containing at
least one displaceable amino hydrogen therein, - tein hydrolysate substituent group for substitu
tion reaction with said amine.
by heating the suspension to a re?uxing temper
.4. The method of converting- the alpha amino
ature under a positive pressure of the uncon
acid content of a protein into an alkali metal salt
densed gases evolved from said suspension will
of a carboxylic acid substituted amine having a
cient only to prevent the entry of atmospheric
gases to the reacting compounds of said suspen-‘ 70 desired mono to poly molecular chain length
sion, the excess pressure of said uncondensed
1 protein hydrolysate substituent group therein,
which comprises suspending a known weight of
the protein in about ten times its weight of water,
of said inorganic base being at least sufficient
adding thereto an- amount of caustic alkali‘ap
to provide su?icient metal ions to neutralize all
carboxylic acid groups of the'alpha amino acids 76 proximating one-half the weight of protein. and
gases being vented to the-atmosphere, the amount
2,411,019
9
an amount of an aliphatic amine having at least
acid content of casein into an alkali metal salt
one amino nitrogen group containing at least one A
of a carboxylic acid substituted amine having a
desired mono to poly molecular chain length pro
tein hydrolysate substituent group therein, which
comprises suspending a known weight of casein
displaceable amino hydrogen therein‘, providing
a large excess of amine over that theoretically re
quired to provide one displaceable amino hydro
gen for each alpha amino nitrogen group in the
alpha amino acid hydrolysate product of said
protein, and heating the suspension to a re?ux
kali and about its same weight of dipropyl amine,
ing temperature under a positive pressure of the
and heating the suspension to a re?uxing tem
in about ten times its weight of water, adding
thereto about one-half its weight of caustic a1
perature approximating 110° C. under a positive
pressure of the uncondensed gases evolved from
the heated suspension su?icient only to exclude
atmospheric gases from the heated suspension,
gases in excess of said pressure being vented to
venting the excess uncondensed gases to the at
the atmosphere, the time interval of said heat
ing being selected within the range 5 to 20 hours 15 mosphere, for a time interval within the range
5 to 20 hours providing the said desired chain
to provide the desired mono to poly molecular
length protein hydrolysate substituent group.
chain length protein hydrolysate substituent
uncondensed gases evolved from the suspension
su?loient only to exclude atmospheric gases from
the heated suspension, the said uncondensed
group.
6. The method of converting the alpha amino
FREDERICK C. BERSWORTH.
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